The National Lung Screening Trial (NLST) reported that low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in adults at high risk for lung cancer. Despite these significant results, there are major concerns regarding lung cancer screening with LDCT. They include high false positivity, cost, and radiation exposure. Blood-based markers are a promising and attractive approach to complement LDCT because of the potential to identify those subjects that may be at increased risk of developing lung cancer, or that may be harboring early and potentially curable lung cancer, or that need to undergo further work-up for their indeterminate nodules. We have identified through a series of discovery and initial validation studies, a set of biomarker candidates with potential for early detection. They include seven protein biomarkers (LRG1, WFDC2, pro-SFTPB, LCN2, IGFBP2, TIMP1, and ANGPTL3) and autoantibodies against Annexin 1, 14-3-3 theta, and LAMR1. As a proof of principle, one of these candidates, pro-SFTPB, was further tested in the Pan- Canadian Early Detection of Lung Cancer Study (PanCan), which consists of 2,537 subjects with high risk of lung cancer with 113 subjects found to have lung cancer. Pro-SFTPB was significantly and independently associated with lung cancer and added to lung cancer prediction with established risk factors. The major goal of our proposal is to increase the efficiency of LDCT. The specific objectives are to develop, refine and validate blood-based biomarkers for: (1) risk assessment of current smokers and former smokers to determine who needs LDCT screening; (2) early detection of lung cancer in current and former smokers based on incidence lung cancer cases; and (3) reduction of the false positive rate of LDCT and increase the positive predictive value of LDCT. To achieve these objectives, we have obtained access to pre-diagnostic samples from cohort studies including the Beta-Carotene and Retinol Efficacy Trial (CARET) and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), and access to two independent screening studies, the PanCan and the German Lung Cancer Screening Intervention Trial (LUSI). Validation studies will proceed in a blinded fashion with combination rules defined in training sets that fit the intended clinical applications.